Contact drug delivery system

ABSTRACT

A drug delivery system is disclosed. The drug delivery system includes a recognitive polymeric hydrogel through which a drug is delivered by contacting biological tissue. The recognitive polymeric hydrogel is formed using a bio-template, which is a drug or is structurally similar to the drug, functionalized monomers, preferably having coamplexing sites, and cross-linking monomers, which are copolymerized using a suitable initiator. The complexing sites of the recognitive polymeric hydrogel that is formed preferably mimics receptor sites of a target biological tissue, biological recognition, or biological mechanism of action. The system in accordance with an embodiment of the intention is a contact lens for delivering a drug through contact with an eye.

RELATED APPLICATIONS

This application claims the priority under 35 U.S.C. §119(e) of theco-pending U.S. Provisional Application Ser. No. 60/692,042, titledSustained Ophthalmic Drug Delivery Via Biomimetic Recognitive ContactLens”, filed Jun. 17, 2005, the U.S. Provisional Application Ser. No.60/736,140, titled “Sustained Ophthalmic Drug Delivery Via BiomimeticRecognitive Contact Lens”, filed Nov. 10, 2005, and the U.S. ProvisionalApplication Ser. No. 60/650,450, titled “Enhanced Loading and ExtendedRelease Contact Lens for Histamine Antagonist Drug Ketotifen”, filedFeb. 4, 2005, all of which are hereby incorporated by reference.

FIELD OF THE INVENTION

The invention relates to drug delivery systems. More specifically, thisinvention relates to systems for and method of time released ophthalmicdrug delivery using contact lenses.

BACKGROUND OF THE INVENTION

Delivering medications via contact lenses has been a prevailing notionsince the inception of using hydrophilic, crosslinked polymer gels onthe surface of the eye. In fact, the first patent in the field from OttoWichterle in 1965 states that “bacteriostatic, bacteriocidal orotherwise medicinally active substances such as antibiotics may bedissolved in the aqueous constituent of the hydrogels to providemedication over an extended period, via diffusion.” However, there isevidence that this notion of a dissolved component in an aqueousconstituent has been around for a much longer period of time. Evidenceexists that honey soaked linen was used in ancient Rome as an ophthalmicdressing in the treatment of disease.

The biggest obstacle to using the fluid entrained in the aqueous portionof the polymer gel is maintaining a significant concentration of drugwithin the fluid to have a therapeutically relevant effect, which isultimately limited by the solubility of the drug. This has been theprimary reason why drug release from contact lenses has not become aclinical or commercial success. To an equivalent extent, the controlover the drug delivery profile and an extended release profile is alsoimportant to therapeutic success and has not been demonstrated usingthese methods. Drug uptake and release by conventional (i.e., currentlyavailable) soft contact lenses can lead to a moderate intraocularconcentration of drug for a very short period of time, but does not workvery well due to a lack of sufficient drug loading and poor control ofrelease. The use of soft, biomimetic contact lens carriers (i.e.,recognitive polymeric hydrogels) described herein has the potential togreatly enhance ocular drug delivery by providing a significant designedand tailorable increase in drug loading within the carrier as well asprolonged and sustained release with increased bioavailability, lessirritation to ocular tissue, as well as reduced ocular and systemic sideeffects.

The ocular bioavailability of drugs applied to the eye is very poor(i.e., typically less than 1-7% of the applied drug results inabsorption with the rest entering the systemic circulation). Factorssuch as ocular protective mechanisms, nasolacrimal drainage, spillagefrom the eye, lacrimation and tear turnover, metabolic degradation, andnon-productive adsorption/absorption, etc., lead to poor drug absorptionin the eye. Currently, more efficient ocular delivery rests on enhancingdrug bioavailability by extending delivery and/or by increasing drugtransport through ocular barriers (e.g., the cornea—a transparent,dome-shaped window covering the front of the eye; the sclera—the tough,opaque, white of the eye; and the conjunctiva—a mucous membrane of theeye with a highly vascularized stroma that covers the visible part ofthe sclera). A topically applied drug to the eye is dispersed in thetear film and can be removed by several mechanisms such as:

-   -   (i) irritation caused by the topical application, delivery        vehicle, or drug which induces lacrimation leading to dilution        of drug, drainage, and drug loss via the nasolacrimal system        into the nasopharynx and systemic circulation (e.g., the rate        drainage increases with volume);    -   (ii) normal lacrimation and lacrimal tear turnover (16% of tear        volume per minute in humans under normal conditions);    -   (iii) metabolic degradation of the drug in the tear film;    -   (iv) corneal absorption of the drug and transport;    -   (v) conjunctival absorption of the drug and scleral transport;    -   (vi) conjunctival ‘non-productive’ absorption via the highly        vascularized stroma leading to the systemic circulation; and    -   (vii) eyelid vessel absorption leading to systemic circulation.        Therefore, due to these mechanisms, a relatively low proportion        of the drug reaches anterior chamber ocular tissue via        productive routes such as mechanisms (iv) and (v).

For posterior eye tissue and back of the eye diseases (e.g., age-relatedmacular degeneration, retinal degeneration, diabetic retinopathy,glaucoma, retinitis pigmentosa, etc.), the amount of drug delivered canbe much less compared to front of the eye disease. To treat back of theeye disease, four approaches have typically been used, topical, oral(systemic delivery), intraocular, and periocular delivery.

Topically applied drugs diffuse through the tear film, cornea/sclera,iris, ciliary body, and vitreous before reaching posterior tissues, butdue to the added transport resistances do not typically lead totherapeutically relevant drug concentrations. However, researchers haveshown that topically applied drugs do permeate through the sclera byblocking corneal absorption and transport. Intravitreal injections(injections into the eye) require repeated injections and have potentialside effects (hemorrhage, retinal detachment, cataract, etc.) along withlow patient compliance. Extended release devices have been used butrequire intraocular surgery and often have the same incidence of sideeffects. Periocular drug delivery is less invasive and also requiresinjections or implant placement for predominantly transscleral delivery.

To overcome most of these protective mechanisms, topical formulationshave remained effective by the administration of very highconcentrations of drug multiple times on a daily basis. For a number ofdrugs high concentrations can lead to negative effects such as burning,itching sensations, gritty feelings, etc., upon exposure of themedication to the surface of the eye as well as increased toxicity andincreased ocular and systemic side effects. However, traditionalophthalmic dosage forms such as solutions, suspensions, and ointmentsaccount for 90% of commercially available formulations on the markettoday. Solutions and suspensions (for less water soluble drugs) are mostcommonly used due to the ease of production and the ability to filterand easily sterilize. Ointments are used to much lesser extent due tovision blurring, difficulty in applying to the ocular surface, andgreasiness. The term “eye drops” herein is meant to refer to alltopological medications administered to a surface of the eye includingbut not limited to solutions, suspensions, ointments and combinationthereof. In addition to the aforementioned problems, drug deliverythrough the use of eye drops does not provide for controlled timerelease of the drug. Eye drops medications typically have a lowresidence time of the drug on the surface of the eye.

The efficacy of topical solutions has been improved by viscosityenhancers that increase the residence time of drugs on the surface ofthe eye, which ultimately lead to increased bioavailability as well asmore comfortable formulations. Also, inclusion complexes have been usedfor poorly soluble drugs, which increase solubility without affectingpermeation.

Other recent delivery methods have included in situ gel-forming systems,corneal penetration or permeation enhancers, conjunctival muco-adhesivepolymers, liposomes, and ocular inserts.

Ocular inserts, in some cases, achieve a relatively stable or constant,extended release of drug. For example, ocular inserts such as Ocusert™(Alza Corp., FDA approved in 1974) consist of a small wafer of drugreservoir enclosed by two ethylene-vinyl acetate copolymer membranes,which is placed in the corner of the eye and provides extended releaseof a therapeutic agent for approximately 7 days (i.e., pilocarpine HCL,for glaucoma treatment reducing intraocular pressure of the eye byincreasing fluid drainage). Lacrisert (Merck) is a cellulose basedpolymer insert used to treat dry eyes. However, inserts have not foundwidespread use due to occasional noticed or unnoticed expulsion from theeye, membrane rupture (with a burst of drug being released), increasedprice over conventional treatments, etc.

Mucoadhesive systems and in-situ forming polymers typically haveproblems involving the anchorage of the carrier as well as ocularirritation resulting in blinking and tear production. Penentrationenhancers may cause transient irritation, alter normal protectionmechanisms of the eye, and some agents can cause irreversible damage tothe cornea.

The novel soft, biomimetic contact lens carriers proposed in this workwill provide a significant increase in drug loading within the gel aswell as prolonged and sustained release. This will lead to prolongeddrug activity and increased bioavailability, reduced systemicabsorption, reduced ocular and systemic side effects, and increasedpatient compliance due to reduced frequency of medication and reducedirregularity of administration (i.e., eye drop volume depends on angle,squeeze force, etc., and has been experimentally verified to be highlyvariable). They will also be able to be positioned easily as well aseasily removed with or without use to correct vision impairment. Sincethey will be positioned on the cornea, this will lead to enhanced comealpermeability as well.

SUMMARY OF THE INVENTION

The present invention is directed to a drug delivery methods andsystems. The drug delivery system includes a recognitive polymerichydrogel through which a drug is delivered by contacting biologicaltissue. The recognitive polymeric hydrogel is formed using abio-template, which is a drug or is structurally similar to the drug,functionalized monomers, preferably having complexing sites, andcross-linking monomers, which are copolymerized using a suitableinitiator, such as described in detail below. The complexing sites ofthe recognitive polymeric hydrogel that is formed preferably mimicsreceptor sites of a target biological tissue, biological recognition, orbiological mechanism of action. The system unitizes what is referred toherein as a biomimetic recognitive polymeric hydrogel.

The system in accordance with an embodiment, the system is an ophthalmicdrug system. The ophthalmic drug system includes soft contact lensesformed from the biomimetic recognitive polymeric hydrogel and that areimpregnated with a drug that can be release over a duration of timewhile in contact with eyes. The invention is directed to both correctiveor refractive contact lenses and non-corrective or non-refractivecontact lenses. While the invention as described herein refers primarilyto ophthalmic drug systems, it is understood that the present inventionhas applications in a number of different contact drug delivery systems.For example, the biomimetic recognitive polymeric hydrogel can be usedin bandages, dressings, and patch-type drug delivery systems to name afew.

In accordance with the embodiments of the invention a hydrogel matrixthat is formed from silicon-based cross-linking monomers, carbon basedor organic-based monomers, macromers or a combination thereof. Suitablecross-linking monomers include but are not limited to Polyethyleneglycol (200) dimethacrylate (PEG200DMA), ethylene glycol dimethacrylate(EGDMA), tetraethyleneglycol dimethacrylate (TEGDMA),N,N′-Methylene-bis-acrylamide and polyethylene glycol (600)dimethacrylate (PEG600DMA). Suitable silicon-based cross-linkingmonomers can include tris(trimethylsiloxy)silyl propyl methacrylate(TRIS) and hydrophilic TRIS derivatives such astris(trimethylsiloxy)silyl propyl vinyl carbamate (TPVC),tris(trimethylsiloxy)silyl propyl glycerol methacrylate (SIGMA),tris(trimethylsiloxy)silyl propyl methacryloxyethylcarbamate (TSMC);polydimethylsiloxane (PDMS) and PDMS derivatives, such as methacrylateend-capped fluoro-grafted PDMS crosslinker, a methacrylate end-cappedurethane-siloxane copolymer crosslinker, a styrene-capped siloxanepolymer containing polyethylene oxide and polypropylene oxide blocks;and siloxanes containing hydrophilic grafts or amino acid residuegrafts, and siloxanes containing hydrophilic blocks or containing aminoacid residue grafts. The molecular structure of these monomers can bealtered chemically to contain moieties that match amino acid residues orother biological molecules. In cases where the above monomers, whenpolymerized with hydrophilic monomers, a solubilizing cosolvent may beused such as dimethylsulfoxide (DMSO), isopropanol, etc. or aprotecting/deprotecting group strategy.

Crosslinking monomer amounts can be from (0.1 to 40%, moles crosslinkingmonomer/moles all monomers); Functional monomers, 99.9% to 60% (molesfunctional monomer/moles all monomers) with varying relative portions ofmultiple functional monomers; initiator concentration ranging from 0.1to 30 wt %; solvent concentration ranging from 0% to 50 wt % (but nosolvent is preferred); monomer to bio-template ratio (M/T) ranging from0.1 to 5,000, preferably 200 to 1,000, with 950 preferred for theketotifen polymers presented herein, under an nitrogen or airenvironment (in air, the wt % of initiator should be increased above 10wt %.

The ophthalmic drug delivery system also includes a bio-template, thatis drug molecules, prodrugs, protein, amino acid, proteinic drug,oligopeptide, polypeptide, oligonucleotide, ribonucleic acid,deoxyribonucleic acid, antibody, vitamin, or other biologically activecompound. This also includes a drug with an attached bio-template. Thebio-template is preferably bound to the hydrogel matrix through one ormore of electrostatic interactions, hydrogen bonding, hydrophobicinteractions, coordination complexation, and Van der Waals forces.

Bio-templates are preferably weakly bound to a hydrogel matrix throughfunctionalized monomer units, macromer units or oligomer units that areco-polymerized into the hydrogel matrix to form receptor locationswithin the hydrogel matrix that resemble or mimic the receptor sites ormolecules associated with the biological target tissue to be treatedwith the drug or the biological mechanism of action

In accordance with the embodiments of the invention, a portion of thebio-template can be washed out from the recognitive hydrogel polymer,loaded with a drug. The polymerization reaction forms a contact lens.For example, the gel is polymerized in a mold or compression casting.After contact lenses are formed they can be used to administer the drugthrough contact with eyes. Alternatively, the recognitive hydrogelpolymer can be formed into contact lenses, washed to remove a portion ofthe bio-template and then loaded with the drug. Where the bio-templateis the drug, the washing step can be illuminated or truncated. Informulations where the bio-template is a drug, the free base form of thedrug or hydrochloride salt of the drug can be used.

In accordance with the method of the present invention, a biomimeticrecognitive polymeric hydrogel is formed by making a mixture or solutionthat includes amounts of a bio-template or drug, functionalized monomeror monomers, cross-linking monomer or monomers and polymerizationinitiator in a suitable solvent or without solvent. Suitable initiatorsinclude water and non-water soluble initiators, but are not limited toazobisisobutyronitrile (AIBN), 2,2-dimethoxy-2-phenyl acetophenone(DMPA), 1-hydroxycyclohexyl phenyl ketone (Irgacure® 184),2,2-dimethoxy-1,2-diphenylethan-1-one (Irgacure 651), ammoniumpersulfate, iniferter such as tetraethylthiuram disulfide, orcombinations thereof. The polymerization can be photo-initiated,thermally-initiated, redox-initiated or a combinations thereof.

The functionalized monomer or monomers complex with the bio-template andcopolymerize with cross-linking monomer or monomers to form a biomimeticrecognitive polymeric hydrogel, such as described above. Functional orreactive monomers useful herein are those which possess chemical orthermodynamic compatibility with a desired bio-template. As used herein,the term functional monomer includes moieties or chemical compounds inwhich there is at least one double bond group that can be incorporatedinto a growing polymer chain by chemical reaction and one end that hasfunctionality that will interact with the bio-template through one ormore of electrostatic interactions, hydrogen bonding, hydrophobicinteractions, coordination complexation, and Van der Waals forces.Functional monomers includes macromers, oligomers, and polymer chainswith pendent functionality and which have the capability of beingcrosslinked to create the recognitive hydrogel. Crosslinking monomerincludes chemicals with multiple double bond functionality that can bepolymerized into a polymer network. Examples of functionalized monomersinclude, but are not limited to, 2-hydroxyethylmethacrylate (HEMA),Acrylic Acid (AA), Acrylamide (AM), N-vinyl 2-pyrrolidone (NVP),1-vinyl-2-pyrrolidone (VP), methyl methacrylate (MMA), methacrylic acid(MAA), acetone acrylamide, 2-ethyl-2-(hydroxymethyl)-1,3-propanedioltrimethacrylate, N-(1,1-dimethyl-3-oxobutyl)acrylamide,2-ethyl-2-(hydroxymethyl)-1,3-propanediol trimethacrylate,2,3-dihydroxypropyl methacrylate, allyl methacrylate,3-[3,3,5,5,5-pentamethyl-1,1-bis[pentamethyldisiloxanyl)oxy]trisiloxanyl]propylmethacrylate,3-[3,3,3-trimethyl-1,1-bis(trimethylsiloxy)disiloxanyl]propylmethacrylate (TRIS), N-(1,1-dimethyl-3-oxybutyl)acrylamide, dimethylitaconate, 2,2,2,-trifluoro-1-(trifluoromethyl)ethyl methacrylate,2,2,2-trifluroethyl methacrylate,methacryloxypropylbis(trimethylsiloxy)methylsilane,methacryloxypropylpentamethyldisiloxane,(3-methacryloxy-2-hydroxypropyloxy)propylbis(trimethylsiloxy)methylsilane,4-t-butyl-2-hydroxycyclohexyl methacrylate, dimethylacrylamide andglycerol methacrylate. Once formed the biomimetic recognitive polymerichydrogel can be formed into contact lenses or as described above thepolymerization reaction forms the contact lenses.

In accordance with further embodiments of the invention, functionalizedmonomers are synthesized or selected by identifying receptor sites ormolecules associated with the target biological tissue to be treated bythe drug or that are associated with metabolizing the drug. Thenfunctionalized portions of the functionalized monomers are synthesizedto chemically and/or structurally resemble or mimic the receptor sitesor molecules that are associated with the biological mechanism of actionof the drug. These functionalized monomers are then copolymerized withthe cross-linking monomer or monomers used to form the hydrogel matrix,such as described above.

After the drug has been depleted from the contact lenses through theeyes, the contact lenses can be re-loaded with the drug by soaking thecontact lenses in the reconstituting drug solution. While the contactlense have been described in detail as being used to deliverantihistamines and other allergy drugs, ophthalmic drug delivery systemsand methods of the present invention can be used to deliver any numberof drugs through contact on the eye and/or systemically.

Drugs that can be delivered by the system and method of the presentinvention include, but are not limited to, Anti-bacterialsAnti-infectives and Anti-microbial Agents (genteelly referred to asantibiotics) such as Penicillins (including Aminopenicillins and/orpenicillinas in conjunction with penicillinase inhibitor),Cephalosporins (and the closely related cephamycins and carbapenems),Fluoroquinolones, Tetracyclines, Macrolides, Aminoglycosides. Specificexamples include, but are not limited to, erythromycin, bacitracin zinc,polymyxin, polymyxin B sulfates, neomycin, gentamycin, tobramycin,gramicidin, ciprofloxacin, trimethoprim, ofloxacin, levofloxacin,gatifloxacin, moxifloxacin, norfloxacin, sodium sulfacetamide,chloramphenicol, tetracycline, azithromycin, clarithyromycin,trimethoprim sulfate and bacitracin.

The ophthalmic drug delivery system and method of the present inventioncan also be used to deliver Non-steroidal (NSAIDs) and SteroidalAnti-inflammatory Agents (genteelly referred to as anti-inflammatoryagents) including both COX-1 and COX-2 inhibitors. Examples include, butare not limited to, corticosteroids, medrysone, prednisolone,prednisolone acetate, prednisolone sodium phosphate, fluormetholone,dexamethasone, dexamethasone sodium phosphate, betamethasone,fluoromethasone, antazoline, fluorometholone acetate, rimexolone,loteprednol etabonate, diclofenac(diclofenac sodium), ketorolac,ketorolac tromethamine, hydrocortisone, bromfenac, flurbiprofen,antazoline and xylometazoline.

The ophthalmic drug delivery system and method of the present inventioncan also be used to deliver Anti-histamines, Mast cell stabilizers, andAnti-allergy Agents (generally referred to as anti-histamines). Examplesinclude, but are not limited, cromolyn sodium, lodoxamide tromethamine,olopatadine HCl, nedocromil sodium, ketotifen fumurate, levocabastineHCL, azelastine HCL, pemirolast (pemirolast potassium), epinastine HCL,naphazoline HCL, emedastine, antazoline, pheniramine, sodiumcromoglycate, N-acetyl-aspartyl glutamic acid and amlexanox.

In yet further embodiments of the invention the ophthalmic drug deliverysystem and method are used to deliver Anti-viral Agents including, butnot limited to, trifluridine and vidarabine; Anti-Cancer Therapeuticsincluding, but not limited to, dexamethasone and 5-fluorouracil (5FU);Local Anesthetics including, but are not limited to, tetracaine,proparacaine HCL and benoxinate HCL; Cycloplegics and Mydriaticsincluding, but not limited to, Atropine sulfate, phenylephrine HCL,Cyclopentolate HCL, scopolamine HBr, homatropine HBr, tropicamide andhydroxyamphetamine Hbr; Comfort Molecules or Molecules (generallyreferred as lubricating agents) to treat Keratoconjunctivitis Sicca (DryEye) including, but not limited to, Hyaluronic acid or hyaluronan (ofvarying Molecular Weight, MW), hydroxypropyl cellulose (of varying MW),gefarnate, hydroxyeicosatetranenoic acid (15-(S)-HETE),phospholipid-HETE derivatives, phoshoroylcholine or other polar lipids,carboxymethyl cellulose (of varying MW), polyethylene glycol (of varyingMW), polyvinyl alcohol (of varying MW), rebamipide, pimecrolimus, ecabetsodium and hydrophilic polymers; Immuno-suppressive andImmuno-modulating Agents including, but not limited to, Cyclosporine,tacrolimus, anti-IgE and cytokine antagonists; and Anti-Glaucoma Agentsincluding beta blockers, pilocarpine, direct-acting miotics,prostagladins, alpha adrenergic agonists, carbonic anhydrase inhibitorsincluding, but not limited to betaxolol HCL, levobunolol HCL,metipranolol HCL, timolol maleate or hemihydrate, carteolol HCL,carbachol, pilocarpine HCL, latanoprost, bimatoprost, travoprost,brimonidine tartrate, apraclonidine HCL, brinzolamide and dorzolamideHCL; decongestants, vasodilaters vasoconstrictors including, but notlimited to epinephrine and pseudoephedrine

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a block diagram showing the steps for making contact lenses,in accordance with the embodiments of the invention.

FIG. 2 illustrates the formation of a recognitive polymeric hydrogel, inaccordance with the embodiments of the invention.

FIG. 3 illustrates a block diagram outlining steps for makingfuntionalized monomer used in the synthesis of recognitive polymerichydrogels, in accordance with the embodiments of the invention.

FIGS. 4A-C illustrate examples of sets of molecules that match, resembleor mimic each other.

FIGS. 5A-B are graphs that compare Ketotifen equilibrium isotherms inwater for a recognitive polymeric hydrogel and a control hydrogel.

FIGS. 5C graphs drug loading for recognitive polymeric hydrogels of thepresent invention against control hydrogels to show the enhanced drugloading for recognitive polymeric hydrogels of the present invention.

FIG. 6 shows a graph of drug release profiles for therapeutic contactlenses, in accordance with the embodiments of the invention.

FIG. 7A-B show graphs of drug release profiles for recognitive polymerichydrogels, in accordance with the embodiments of the invention

DETAILED DESCRIPTION OF A PREFERRED EMBODIMENT

Hydrogels are insoluble, cross-linked polymer network structurescomposed of hydrophilic homo- or hetero-co-polymers, which have theability to absorb significant amounts of water. Consequently, this is anessential property to achieve an immunotolerant surface and matrix(i.e., with respect to protein adsorption or cell adhesion). Due totheir significant water content, hydrogels also possess a degree offlexibility very similar to natural tissue, which minimizes potentialirritation to surrounding membranes and tissues.

The hydrophilic and hydrophobic balance of a gel carrier can be alteredto provide tunable contributions that present different solventdiffusion characteristics, which in turn influence the diffusive releaseof a drug contained within the gel matrix. In general, one maypolymerize a hydrophilic monomer with other less hydrophilic or morehydrophobic monomers to achieve desired swelling properties.

These techniques have led to a wide range of swellable hydrogels.Knowledge of the swelling characteristics is of major importance inbiomedical and pharmaceutical applications since the equilibrium degreeof swelling influences the diffusion coefficient through the hydrogel,surface properties and surface mobility, mechanical properties, andoptical properties. Drug release depends on two simultaneous rateprocesses: water migration into the network and drug diffusion outwardthrough the swollen gel.

Soft contact lenses are made of hydrogels. The typical materialproperties for contact lenses involve a number of considerations such asoptical quality (good transmission of visible light), high chemical andmechanical stability, manufacturability at reasonable cost, high oxygentransmissibility, tear film wettability for comfort, and resistance toaccumulation of protein and lipid deposits, as well as a suitablecleaning and disinfecting scheme.

Soft contact lenses typically consist of poly(2-hydroxyethylmethacrylate) (PHEMA). Other lens materials include HEMA copolymerizedwith other monomers such as methacrylic acid, acetone acrylamide, andvinyl pyrrolidone. Also, commonly used are copolymers of vinylpyrrolidone and methyl methacrylate as well as copolymers of glycerolmethacrylate and methyl methacrylate. Minor ingredients have included avariety of other monomers as well as cross-linking agents.

The immersion and soaking of soft contact lenses in drug solutions hasshown promise in the increase of drug bioavailability with aminimization of side effects. However, the materials and constituentchemistry of the macromolecular chains and subsequent interaction withdrugs is random and typically leads to poor drug loading.

In order to address the above referenced shortcomings, the presentinvention is directed to the use of biomimetic imprinting of hydrogelsto make hydrogels matrices that can selectively bind a drug throughcomplexing sites leading to improved loading of a drug and controlledtime release of the drug. These hydrogels are referred to as recognitivepolymeric hydrogels. The polymerization reaction forms the contactlenses, which can be used to administer drugs through contact with theeyes, thereby replacing traditional eye drop therapies. Alternatively,the recognitive polymeric hydrogels can be formed or fashioned intocontact lenses which can be used to administer drugs through contactwith the eyes, thereby replacing traditional eye drop therapies or othermechanisms of delivery.

For example, ketotifen fumurate is a potent fast acting and highlyselective histamine H1 antagonists with a sustained duration of action.Levocabastine and ketotifen fumurate inhibits itching, redness, eyelidswelling, tearing, and chemosis induced by conjunctival provocation withallergens and histamine. With topical application in the form of eyedrops, absorption is incomplete and bioavailability is low. Thus, thedose is usually administered multiple times daily. Also, due to a highconcentration of drug and other constituents of the ophthalmicsuspension preparation, patients are advised not to wear soft contactlenses. Accordingly, a soft contact lens that could be used toadminister ketotifen fumurate would not only enhance the efficacy of thetreatment, but also allow allergy sufferers to wear contact lenses.

Referring to FIG. 1 which is a block diagram 100 outlining steps formaking contact lenses, in accordance with the embodiments of theinvention and FIG. 2 which is a graphical representation of forming arecognitive polymeric hydrogel 221. In the step 101, the recognitivehydrogel matrix 221 is formed. The recognitive hydrogel 221 is formed bygenerating a solution 200 comprising one or more bio-template 201, oneor more functionalized monomers 203 and 203′, one or more cross-linkingmonomers 205 with or without a solvent. In the solution 200′ thefunctionalized monomers 203 and 203′ complexes with the bio-templates201. A suitable initiator or mixture initiators 207 is used toco-polymerize the functionalized monomers 203 and 203′ with across-linking monomer 205 to form the loaded hydrogel 220 comprising ahydrogel matrix 221 with bio-templates 201 complexing at site 209through the hydrogel matrix 221.

Preferably, the bio-templates are complexed with the hydrogel matrix 221through weak or non-covalent interactions, as explained above, wherebythe bio-templates can be washed or rinsed from the complexed hydrogel220 to form an un-complexed recognitive polymeric hydrogel 221, whichhas vacant complexing sites 209 that can be used to complex drugmolecules that are structurally and/or chemically similar to thebio-templates 201. It will be clear from the discussions above and belowthat the bio-templates can be a drug and, therefore, washing thebio-templates from the hydrogel matrix 221 may not be necessary for alldrug delivery systems that are synthesized.

Still referring to both FIG. 1 and FIG. 2, after the recognitivehydrogel 221 is formed, in the step 101, in the step 103 the recognitivehydrogel 221 can be formed into contact lenses using any technique knownin the art. Its is understood that the step the step 103 is notnecessary, when the polymerization reaction forms the contact lenses,such as described previously. Where the bio-template is a drug, thecontact lenses can be placed in contact with eyes in the step 107 toadminister or deliver the drug to or through the eyes. Where, thebio-template 201 has been washed from the recognitive hydrogel matrixprior to or after the step 103 of forming the contact lenses from therecognitive hydrogel matrix, then in the step 109 or the step 105,respectively, the recognitive hydrogel matrix or the contact lenses areloaded with a drug. The recognitive hydrogel matrix or the contactlenses can be loaded with the drug by soaking the recognitive hydrogelmatrix or the contact lenses in an aqueous drug solution.

Now referring to FIG. 2 and FIG. 3. In accordance with furtherembodiments of the invention prior to the step of making an ophthalmicdrug delivery system, such as described with reference to FIG. 1, in thestep 301 the target tissue to be treated with the drug or biologicalmechanism of action is studied to determine the types of molecules orfunctional groups that are associated with the action of the drug at thetarget tissue to effect the target tissue. Based on this information, inthe step 303, funtionalized monomers are synthesized with functionalgroups that mimic or resemble molecules or functional groups that areassociated with the action of the drug at the target tissue. Thefunctionalized monomers with the functional groups that mimic orresemble molecules or functional groups that are associated withmetabolizing the drug at the target tissue are then used to synthesize adrug delivery system, such as described above with reference to FIG. 1.The biomimetic approach is the processes of mimicking biologicalrecognition or exploiting biological mechanisms. Specifically, it is theprocess of coordinating biological molecular recognition, interactions,or actions to design materials that can be structurally similar toand/or function in similar ways as biological structures.

FIGS. 4A-C illustrate examples of sets of molecules that match, resembleor mimic each other. With reference to the bio-mimetic approach forsynthesizing recognitive hydrogel polymers described above, acrylic acidcan be used to mimic aspartic acid (FIG. 4A), acrylaminde can be used tomimic asparagine (FIG. 4B) and N-vinyl pyrrolidinone can be used tomimic tyrosine (FIG. 4C). Aspartic acid, asparagine, and tyrosine areknown to be of the group of amino acids providing the non-covalentinteractions in the ligand binding pocket for histamine. For example,structural analysis of ligand binding pockets and amino acids involvedin multiple non-covalent binding points provide one of many rationalframeworks to synthesize recognitive networks from functional monomers.Antihistamine has been shown to bind more tightly and have a higheraffinity than histamine for the histamine binding pocket.

EXAMPLE

Materials and Methods: Acrylic Acid (AA), Acrylamide (AM),N-Vinyl-2-Pyrrolidone (NVP) and 2-hydroxyethylmethacrylate (HEMA),Azobisisobutyronitrile (AIBN), and Ketotifen Fumarate were purchasedfrom Sigma-Aldrich. Polyethylene glycol (200) dimethacrylate (PEG200MA)was purchased from Polysciences, Inc. All chemicals were used asreceived. Polymer and copolymer networks were made using variousmixtures of above monomers (e.g. Poly(AA-co-AM-HEMA-PEG200DMA),Poly(AA-co-HEMA-co-PEG200DMA), Poly (AM-co-HEMA-co-PEG200DMA),Poly(AA-co-AM-co-NVP-co-HEMA-PEG200DMA)). Current work is directed toproducing networks that can also be used in the formation of contactlens for anti-histamines with monomers and copolymers of molecules suchas N-vinyl 2-pyrrolidone (NVP), 1-vinyl-2-pyrrolidone (VP), methylmethacrylate (MMA), methacrylic acid (MAA), acetone acrylamide, ethyleneglycol dimethacrylate (EGDMA), 2-ethyl-2-(hydroxymethyl)-1,3-propanedioltrimethacrylate, N-(1,1-dimethyl-3-oxobutyl)acrylamide,2-ethyl-2-(hydroxymethyl)-1,3-propanediol trimethacrylate,2,3-dihydroxypropyl methacrylate, allyl methacrylate any other suitablemonomers, such as those referenced previously.

Accurate quantities of monomers, template molecules and crosslinkerswere added in that order, and the mixture was sonicated to obtain ahomogenous solution. In particular, a typical formulation consisted of 5mole % cross-linking monomer (PEG200DMA) in a solution of Acrylamide(M), HEMA (M), Ketotifen (T), with an M/T ratio of approximately 950(92% HEMA, 1% of remaining monomers, and approximately 1 mole % drugdepending on the M/T ratio). Controls were also prepared without thetemplate. Next, initiator AIBN was added in low light conditions, andthe solutions were allowed to equilibrate for 12 hours in darkness. Thisstep allowed the monomers and template to orient them selves and reachtheir free energy minima, thus beginning the configurational imprintingat the molecular level. However, this step occurs very quickly such ason the order of minutes.

The solutions were then transferred to an MBRAUN Labmaster 130 1500/1000Glovebox, which provides an inert nitrogenous and temperature-controlledatmosphere for free-radical photopolymerization. With an increase inphotoinitiator wt. %, this step can proceed in air. The solutions wereuncapped and left open to the nitrogen until the oxygen levels reachednegligible levels (<0.1 ppm). The solutions were inserted into glassmolds (6 in. by 6 in.) separated by a Teflon frame 0.8 mm wide, asmeasured by a Vernier caliper. The glass plates were coated withchlorotrimethylsilane in order to prevent the polymer matrix fromsticking to the glass, as it demonstrates a strong adherent tendency dueto hydrogen bonding. Polymerization was carried out for ten minutes at325 V using a Dymax UV light source. The intensity of radiation was 40mW/cm², as measured with a radiometer, and the temperature was 36° C.,as measured by a thermocouple.

The polymer was peeled off the glass plates with flowing deionized water(Millipore, 18.2 mO.cm, pH 6), and then was allowed to soften forapproximately 10 minutes. Circular discs were cut using a Size 10 corkborer (13.5 mm), and were typically washed for 5 days in a continuousflow system using deionized water. All washes proceeded until theabsence of detectable drug was verified by spectroscopic monitoring. Toobtain dry weights, some discs were allowed to dry under laboratoryconditions (20° C.) for 36 hours. The discs were then transferred to avacuum oven (27 in. Hg, 33-34° C.) for 48 hours until they were dry(less than 0.1 wt % difference).

Polymer penetrant uptake and swelling data were obtained in deionizedwater with samples taken every 5 min. for the first hour, and then everyhour for 10 hours until equilibrium was reached. As the gel was removedfrom the water, excess surface water was dabbed with a dry Kim wipe. Theequilibrium weight swelling ratio at time t, q, for a given gel wascalculated using the weights of the gels at a time and the dry polymerweights, respectively, using equations based on Archimedes principle ofbuoyancy. Dynamic and Equilibrium Template Binding: Dynamic templatedrug molecule binding was performed until equilibrium had beenestablished for each system. Stock solutions of drug with aconcentration 2 mg/ml were prepared and diluted with deionized water toproduce 0.1, 0.2, 0.3, 0.4 and 0.5 mg/ml solutions. Each solution wasvortexed for 30 seconds to provide homogeneity, and initial UVabsorbances were noted. Gels were then inserted into the vials and wereplaced on a Stovall Belly Button Orbital Shaker over the entire durationof the binding cycle to provide adequate mixing. A 200 μl aliquot ofeach sample was placed in a Corning Costar UV-transparent microplate,and absorbance readings were taken using a Biotek Spectrophotometer at268 nm. After measurement, the reading sample was returned to theoriginal samples, to avoid fluctuations in concentrations due tosampling methods.

Dynamic Release Studies: In obtaining the preliminary results, dynamicrelease studies were conducted in DI water, artificial lacrimal fluid(6.78 g/L NaCl, 2.18 g/L NaHCO₃, 1.38 g/L KCl, 0.084 g/L CaCl₂2H₂O, pH8), and lysozyme (1 mg/ml) in artificial lacrimal fluid. Gels which hadbeen drug loaded were placed in 30 ml of DI water, and the solutionswere continuously agitated with a Servodyne mixer (Cole PalmerInstrument Co.) at 120 rpm. Release of drug was monitored at 268 nm bydrawing 200 μL of solution into a 96-well Corning Costar UV-transparentmicroplate, and measurements were taken in a Synergy UV-VisSpectrophotometer (Biotek). Absorbances were recorded for three samples,averaged, and corrected by subtracting the relevant controls. Solutionswere replaced after each reading. Separate studies were conducted todetermine if infinite sink conditions existed and those conditions werematched throughout all experiments.

Polymerization Kinetics and Network Formation: Solutions were preparedwith 0, 0.1, 0.5, and 1 mole percent of Ketotifen in the initial monomersolutions. Kinetic studies were conducted with a differential scanningphotocalorimeter (DPC, Model No. DSC Q100, TA Instruments with Mercurylight source). Samples of 10 μl, were placed in an aluminum hermetic panand purged with nitrogen (flow rate 40 ml/min) in order to preventoxidative inhibition. They were allowed to equilibrate at 35°° C. for 15minutes, before shining UV light at 40 mW/cm2 for 12 minutes.

The heat that evolved was measured as a function of time, and thetheoretical enthalpy of the monomer solution was used to calculate therate of polymerization, Rp, in units of fractional double bondconversion per second. Integration of the rate of polymerization curveversus time yielded the conversion as a function of time or reactionrate. The presence of template and a solvent, if used, was accounted forin the calculations, as it did not participate in the polymerizationreaction. Experimental results were reproducible and the greatest sourceof error involved the assumed theoretical enthalpies in the calculationsof the rate of polymerization and conversion. For all studies, theenthalpies were assumed to have errors of +5%. The assumptions in thecopolymerization of two monomers (i.e., functional and cross-linkingmonomers) were that each monomer had equal reactivity and thetheoretical enthalpy derived for a co-monomer mixture was an average ofthe enthalpies of individual monomers. The theoretical enthalpy ofmethacrylate double bonds was equal to 13.1 kcal mole-1 and thetheoretical enthalpy of acrylate double bonds was equal to 20.6 kcalmole-1.

RESULTS

FIG. 5A shows a graph 500 of the equilibrium binding isotherm forKetotifen in water for Poly(acrylamide-co-HEMA-co-poly(ethyleneglycol)200 dimethacrylate)hydrogel networks with a cross-linkingpercentage of 5%. N=3 and T=25° C. The recognitive hydrogel network isrepresented by the line 501 and the control hydrogel network isrepresented by the line 503. Percentage denotes percent mole crosslinkerper mole total monomers in feed.

FIG. 5B shows a graph 510 of the equilibrium binding isotherm forKetotifen in water for Poly(acrylic acid-co-HEMA-co-poly(ethyleneglycol)200 dimethacrylate) hydrogel networks with a cross-linkingpercentage of 5%. N=3 and T=25° C. The recognitive hydrogel networks isrepresented by line 511 and the control hydrogel network is representedby line 513. Percentage denotes percent mole crosslinker per mole totalmonomers in feed.

FIG. 5C shows a graph 540 of enhanced Loading of Ketotifen for MultipleMonomer Gels for Poly(n-co-HEMA-co-poly(ethylene glycol)200dimethacrylate) Networks. The Functional monomers uses are acrylic acid,acrylamide, NVP, or an equal mole mixture of both. The Recognitivenetworks are shown as hatched bars 543 and the Control networks areshown as clear bars 541.

FIG. 6 shows a graph 600 of Tailorable Release Profiles Of TherapeuticContact Lenses for Poly(n-co-HEMA-co-poly(ethylene glycol)200dimethacrylate) Networks in Artificial Lacrimal Fluid, where n is AM(represented by circles ), AA (represented by squares),AA-AM(represented by triangles), and NVP-AA-AM (represented by diamonds)recognitive networks respectively. Results demonstrate approximatelyconstant release rate of ketotifen fumurate for 1 to 5 days.

FIG. 7A shows a graph 700 of Release Data forPoly(AM-co-HEMA-co-poly(ethyleneglycol)200 dimethacrylate) RecognitiveNetworks. Fraction of Mass Released in Artificial Lacrimal SolutionWith/Without Lysozyme.

FIG. 7B shows a graph 725 of Release Data forPoly(AM-co-AA-co-HEMA-co-poly(ethyleneglycol)200 dimethacrylate)Networks Mass of Drug Released in Artificial Lacrimal Solution.

I. Enhanced Loading and Performance of Multiple Monomer Mixtures In thepreliminary work, hydrogels were produced with enhanced loading forketotifen fumarate. Polymers were made with the following monomers:acrylic acid (AA), N-vinyl 2-pyrrolidone (NVP), acrylamide (AM),2-hydroxyethylmethacrylate (HEMA), and polyethylene glycol (200)dimethacrylate (PEG200DMA).

We hypothesized that gels composed of multiple functional monomers wouldoutperform those composed of single functional monomers. Foranti-histamine recognitive polymers, this would better mimic the dockingsite of histamine at the molecular level providing all the relevantfunctionality necessary for non-covalent interactions. We have provedthat loading properties of gels are improved with multiple monomermixtures.

Gels of multiple complexation points with varying functionalitiesoutperformed the gels formed with less diverse functional monomer andshowed the highest maximum bound of ketotifen and highest differenceover control gels. Equilibrium binding isotherms forPoly(AM-co-AA-co-HEMA-co-PEG200DMA) networks demonstrate enhancedloading with a factor of 2 times increase in the loading of drugcompared to conventional networks (i.e., gels prepared without templateand comparable to existing contact lenses) depending on polymerformulation and polymerization conditions. Poly(AM-co-HEMA-co-PEG200DMA)networks demonstrated a factor of 2 or 100% increase in the loading ofdrug compared to control networks with lower bound amounts.Poly(AA-co-HEMA-co-PEG200DMA) networks show a factor of 6 times increaseover control in the loading of ketotifen with the overall drug boundbeing the lowest of the polymer formuations studies (approximately 33%less ketotifen loading than the AM functionalized network).

For all systems, an increase in the amount of loaded drug has beenconfirmed, but with the most biomimetic formulation(Poly(AA-co-AM-co-NVP-co-HEMA-PEG200DMA)) a significant increase inloading is demonstrated yielding the greatest loading potential (thehighest loading achieved to date and 6x over control networks due tomultiple binding points with varying functionalities) (FIG. 5C).

II. Dynamic Drug Release Profiles

Dynamic release profiles in artificial lacrimal solution and anartificial lacrimal solution with protein, demonstrated extended releaseof a viable therapeutic concentration of ketotifen. Release studiesconfirmed that release rates can be tailored via type and amount offunctionality and extended from one to five days. FIG. 6 highlightsnormalized data of the fraction of drug released versus time (massdelivered at time t divided by the mass delivered at infinite time). Forpoly(n-co-HEMA-co-PEG200DMA) networks (where n was AA-co-AM, AM, or AA),the release of drug showed a relatively constant rate of release forapproximately 1 day, with little difference in the release profile.However, the most structurally biomimetic network,poly(AA-co-AM-co-NVP-co-HEMA-PEG200DMA), exhibited a five fold increasein the extended release profile (i.e., approximately 5 days).

It is hypothesized that providing all the relevant functionality to themimicked docking site with the proposed polymer synthesis techniqueaffords a higher affinity of the drug for the network and thus an evenslower release of drug compared to control networks. Furthermore, a fiveto seven day release profile fits quite well into the time usage ofone-week extended-wear soft contacts.

It has been demonstrated that the loading of drug can be controlled bythe type, number, and diversity of functionality within the network. Theloading (and hence the mass delivered) can also be controlled by theinitial loading concentration of the drug. We have demonstrated controlover the cumulative mass of drug released by changing the loadingconcentration. By considering the relative size of our gels (i.e., gelswere slightly bigger than normal lenses) and mass of drug released incomparison to typical ophthalmic eye drop dosages (ketotifen 0.25 mg/mLof solution with one drop every 8 hours), the preliminary resultsrevealed that a therapeutically relevant dosage could be delivered forextended periods of time.

To investigate the effect of protein on dynamic release, we choselysozyme as a model protein since it is the largest protein component intear fluid. FIGS. 7A-B highlights the poly(AM-co-HEMA-co-PEG200DMA)network release profile in artificial lacrimal solution with lysozyme,which leads to a factor of 5 increase in the duration of release. Forthe most structurally biomimetic network,poly(AA-co-AM-co-NVP-co-HEMA-PEG200DMA), this could lead to a sustainedrelease approaching 25 days. These studies demonstrate that the time ofrelease may be delayed even further in an in vivo environment, leadingto a substantial increase in applicability of contact lens oculardelivery.

III. Polymerization Reaction Analysis

The rate of polymerization for a given conversion decreased forincreasing mole percentage of template molecule in pre-polymerizationmonomer solution. Thus, the formation of polymer chains and the enhancedloading due to the configurational biomimetic effect may be related tothe propagation of polymer chains. The template molecule poses physicalconstraints to free radical and propagating chain motion and henceeffectively lowers the rate of polymerization in the creation of ligandbinding pockets. These results show that CBIP is reflected at themolecular level. For a given conversion, the rate of polymerization waslower for the multiple functional monomer pre-polymerization mixturesthan the single monomer mixtures. We hypothesize that CBIP with multiplemonomers results in the formation of better ligand-binding pockets withenhanced loading properties which leads to slower rates ofpolymerization.

IV Equilibrium Swelling Profiles and Mechanical Property Analysis:

Equilibrium swelling studies in DI water and 0.5 mg/ml concentratedketotifen solution) indicated that recognitive and control networks werestatistically the same and that 40% of the swollen gels is water, whichindicates that the comfort of wearing and oxygen permeability of thesegels is in agreement with conventional contact lenses. These studiesindicated that CBIP, and not an increased porosity or surface area ofthe gel, is responsible for the enhanced loading properties. It alsodemonstrated that the loading process does not affect the rate ofswelling of the polymer matrix.

Further studies on the mechanical properties of the gels have showncomparable storage and loss moduli, glass transition temperatures anddamping factors to that of conventional contact lenses (data not shown).Each gel produced was optically clear and had sufficient viscoelasticityto be molded in thin films (for refractive differences)

CONCLUSION

Polymerization kinetics in the presence of the template revealmechanisms of interaction as well as provide criteria with which othertemplate-monomer systems can be chosen experimentally. The use of abiomimetic approach for synthesizing recognitive hydrogel polymers hasled to the development of an ophthalmic drug delivery system usingcontact lenses formed from the recognitive hydrogel polymer. Theophthalmic drug delivery system of the present invention can provideimproved bioavailability and efficacy of drug delivery and exhibitcontrolled time release of the drug. The ophthalmic drug delivery systemcan be tailored to exhibit properties suitable for the intended drugtherapy and has a potential to replace traditional eye drop therapiesand other methods.

The present invention has been described in terms of specificembodiments incorporating details to facilitate the understanding of theprinciples of construction and operation of the invention. Suchreference herein to specific embodiments and details thereof is notintended to limit the scope of the claims appended hereto. It will beapparent to those skilled in the art that modifications can be made inthe embodiment chosen for illustration without departing from the spiritand scope of the invention. Specifically, it will be apparent to one ofordinary skill in the art that the device of the present invention couldbe implemented in several different ways and the apparatus disclosedabove is only illustrative of the preferred embodiment of the inventionand is in no way a limitation.

1. A method for making a drug delivery system, the method comprising: a)forming a recognitive polymeric hydrogel; and b) forming a recognitivepolymeric hydrogel into contact lenses.
 2. The method of claim 1,wherein forming a recognitive polymeric hydrogel comprises forming asolution comprising amounts of a bio-template, a functionalized monomercross-linking monomer and initiating copolymerization of thefunctionalized monomer and cross-linking monomer.
 4. The method of claim2, further comprising washing a portion of the bio-template from therecognitive polymeric hydrogel and loading the recognitive polymerichydrogel with a drug.
 5. The method of claim 4, wherein the drug isselected from the group consisting of an antibiotic, ananti-inflammatory, an antihistamine, an antiviral agent, a cancer drug,an anesthetic, a cycloplegic, a mydriatics, a lubricant agent, ahydrophilic agent, a decongestant, a vasoconstrictor, vasodilater, anImmuno-suppressant, an immuno-modulating agent and an anti-glaucomaagent.
 6. The method of claim 2, further comprising washing a portion ofthe bio-template from the contact lenses and loading the contact lenseswith a drug by soaking the contact lenses in an aqueous drug solution.7. The method of claim 6, wherein the drug a drug selected from thegroup consisting of an antibiotic, an anti-inflammatory, anantihistamine, an antiviral agent, a cancer drug, an anesthetic, acycloplegic, a mydriatics, a lubricant agent, a hydrophilic agent, adecongestant, a vasoconstrictor, vasodilater, an Immuno-suppressant, animmuno-modulating agent and an anti-glaucoma agent.
 8. The method ofclaim 2, wherein the bio-template is a drug.
 9. The method of claim 8,wherein the drug is selected from the group consisting of an antibiotic,an anti-inflammatory, an antihistamine, an antiviral agent, a cancerdrug, an anesthetic, a cycloplegic, a mydriatics, a lubricant agent, ahydrophilic agent, a decongestant, a vasoconstrictor, vasodilater, anImmuno-suppressant, an immuno-modulating agent and an anti-glaucomaagent.
 10. The method of claim 2, further comprising identifyingmolecules associated with a target biological tissue and synthesizingthe functionalized monomer with functional groups that are structurallysimilar the molecules.
 11. A method of dispensing a drug comprising: a)forming a recognitive polymeric hydrogel matrix impregnated with a drug;and b) placing the recognitive polymeric hydrogel is contact with abiological tissue to dispense the drug.
 12. The method of claim 11,wherein the drug is selected from the group consisting of an antibiotic,an anti-inflammatory, an antihistamine, an antiviral agent, a cancerdrug, an anesthetic, a cycloplegic, a mydriatics, a lubricant agent, ahydrophilic agent, a decongestant, a vasoconstrictor, vasodilater, anImmuno-suppressant, an immuno-modulating agent and an anti-glaucomaagent.
 13. The method of claim 11, wherein forming the recognitivepolymeric hydrogel matrix comprises generating a solution comprisingamounts of a bio-template, a functionalized monomer cross-linkingmonomer and initiating co-polymerization of the functionalized monomerand cross-linking monomer.
 14. The method of claim 13, wherein formingthe recognitive polymeric hydrogel matrix is a contact lens.
 15. Themethod of claim 13, wherein the bio-template is a drug.
 16. The methodof claim 15, wherein the drug is selected from the group consisting ofan antibiotic, an anti-inflammatory, an antihistamine, an antiviralagent, a cancer drug, an anesthetic, a cycloplegic, a mydriatics,vasodilater, a lubricant agent, a hydrophilic agent, a decongestant, avasoconstrictor, an immuno-suppressant, an immuno-modulating agent andan anti-glaucoma agent.
 17. The method of claim 11, further comprisingreloading the recognitive polymeric hydrogel matrix with the drug bysoaking the recognitive polymeric hydrogel matrix in an aqueous solutionof the drug.
 18. A drug delivery system comprising a contact lens, thecontact lens comprising a hydrogel matrix with complexing sites thatcomplex a drug and release the drug from the hydrogel matrix over timewhile in contact with a surface of an eye.
 19. The drug delivery systemof claim 18, wherein the hydrogel matrix comprises silicon-base polymerchains.
 20. The drug delivery system of claim 18, wherein the complexingsites comprise amino acid functional groups.
 21. The drug deliverysystem of claim 18, wherein the group consisting of an antibiotic, ananti-inflammatory, an antihistamine, an antiviral agent, a cancer drug,an anesthetic, a cycloplegic, a mydriatics, a lubricant agent, ahydrophilic agent, a decongestant, a vasoconstrictor, vasodilater, anImmuno-suppressant, an immuno-modulating agent and an anti-glaucomaagent.
 22. The drug delivery system of claim 18, wherein the drug isKetotifen.